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1.
Leukemia ; 32(3): 719-728, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-28860655

RESUMEN

Despite therapeutic advances, multiple myeloma remains incurable, with limited options for patients with refractory disease. We conducted a large, multi-cohort clinical trial testing various doses and treatment schedules of pomalidomide and dexamethasone (Pom/dex) in patients with refractory multiple myeloma. Overall, 345 patients were enrolled to six cohorts based on number and type of prior lines of therapy, pomalidomide dose and schedule. Median prior lines of therapy were three with near universal prior exposure to proteasome inhibitors and/or immunomodulatory drugs. A confirmed response rate of 35% was noted for all cohorts (range 23-65%) with higher responses in cohorts with fewer prior lines of therapy. Median time to confirmed response was ⩽2 months and the longest progression-free survival and overall survival seen in any cohort were 13.1 and 47.9 months, respectively. Observed adverse reactions were as expected, with myelosuppression and fatigue being the most common hematologic and non-hematologic adverse events (AEs), respectively. Longer durations of treatment and response, higher response rates and fewer AEs were noted with the 2 mg pomalidomide dose. This is the longest follow-up data for Pom/dex in refractory multiple myeloma and will help shape the real-world utilization of this regimen.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Dexametasona/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , Retratamiento , Análisis de Supervivencia , Talidomida/administración & dosificación , Talidomida/análogos & derivados , Resultado del Tratamiento
2.
Blood Cancer J ; 7(5): e565, 2017 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-28548645

RESUMEN

Although ibrutinib is highly effective in Waldenstrom macroglobulinemia (WM), no complete remissions in WM patients treated with ibrutinib have been reported to date. Moreover, ibrutinib-resistant disease is being steadily reported and is associated with dismal clinical outcome (overall survival of 2.9-3.1 months). To understand mechanisms of ibrutinib resistance in WM, we established ibrutinib-resistant in vitro models using validated WM cell lines. Characterization of these models revealed the absence of BTKC481S and CXCR4WHIM-like mutations. BTK-mediated signaling was found to be highly attenuated accompanied by a shift in PI3K/AKT and apoptosis regulation-associated genes/proteins. Cytotoxicity studies using the AKT inhibitor, MK2206±ibrutinib, and the Bcl-2-specific inhibitor, venetoclax±ibrutinib, demonstrated synergistic loss of cell viability when either MK22016 or venetoclax were used in combination with ibrutinib. Our findings demonstrate that induction of ibrutinib resistance in WM cells can arise independent of BTKC481S and CXCR4WHIM-like mutations and sustained pressure from ibrutinib appears to activate compensatory AKT signaling as well as reshuffling of Bcl-2 family proteins for maintenance of cell survival. Combination treatment demonstrated greater (and synergistic) antitumor effect and provides rationale for development of therapeutic strategies encompassing venetoclax+ibrutinib or PI3K/AKT inhibitors+ibrutinib in ibrutinib-resistant WM.


Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/farmacología , Mutación Missense , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas c-akt/biosíntesis , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Pirazoles/farmacología , Pirimidinas/farmacología , Receptores CXCR4 , Sulfonamidas/farmacología , Regulación hacia Arriba/efectos de los fármacos , Macroglobulinemia de Waldenström , Adenina/análogos & derivados , Agammaglobulinemia Tirosina Quinasa , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Piperidinas , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Regulación hacia Arriba/genética , Macroglobulinemia de Waldenström/tratamiento farmacológico , Macroglobulinemia de Waldenström/genética , Macroglobulinemia de Waldenström/metabolismo , Macroglobulinemia de Waldenström/patología
3.
Blood Cancer J ; 6(11): e492, 2016 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-27813535

RESUMEN

The survival of Waldenstrom macroglobulinemia (WM) tumor cells hinges on aberrant B-cell receptor (BCR) and MYD88 signaling. WM cells upregulate the proteasome function to sustain the BCR-driven growth while maintaining homeostasis. Clinically, two treatment strategies are used to disrupt these complementary yet mutually exclusive WM survival pathways via ibrutinib (targets BTK/MYD88 node) and bortezomib (targets 20 S proteasome). Despite the success of both agents, WM patients eventually become refractory to treatment, highlighting the adaptive plasticity of WM cells and underscoring the need for development of new therapeutics. Here we provide a comprehensive preclinical report on the anti-WM activity of VLX1570, a novel small-molecule inhibitor of the deubiquitinating enzymes (DUBs), ubiquitin-specific protease 14 (USP14) and ubiquitin carboxyl-terminal hydrolase isozyme L5 (UCHL5). Both DUBs reside in the 19 S proteasome cap and their inhibition by VLX1570 results in rapid and tumor-specific apoptosis in bortezomib- or ibrutinib-resistant WM cells. Notably, treatment of WM cells with VLX1570 downregulated BCR-associated elements BTK, MYD88, NFATC, NF-κB and CXCR4, the latter whose dysregulated function is linked to ibrutinib resistance. VLX1570 administered to WM-xenografted mice resulted in decreased tumor burden and prolonged survival (P=0.0008) compared with vehicle-treated mice. Overall, our report demonstrates significant value in targeting USP14/UCHL5 with VLX1570 in drug-resistant WM and carries a high potential for clinical translation.


Asunto(s)
Azepinas/administración & dosificación , Compuestos de Bencilideno/administración & dosificación , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Macroglobulinemia de Waldenström/tratamiento farmacológico , Adenina/análogos & derivados , Apoptosis/efectos de los fármacos , Bortezomib/administración & dosificación , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Enzimas Desubicuitinizantes/antagonistas & inhibidores , Enzimas Desubicuitinizantes/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Piperidinas , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Transducción de Señal/efectos de los fármacos , Ubiquitina Tiolesterasa/genética , Macroglobulinemia de Waldenström/genética , Macroglobulinemia de Waldenström/patología
6.
Blood Cancer J ; 4: e260, 2014 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-25382610

RESUMEN

Neem leaf extract (NLE) has medicinal properties, which have been attributed to its limonoid content. We identified the NLE tetranorterpenoid, nimbolide, as being the key limonoid responsible for the cytotoxicity of NLE in various preclinical models of human B-lymphocyte cancer. Of the models tested, Waldenströms macroglobulinemia (WM) cells were most sensitive to nimbolide, undergoing significant mitochondrial mediated apoptosis. Notably, nimbolide toxicity was also observed in drug-resistant (bortezomib or ibrutinib) WM cells. To identify putative targets of nimbolide, relevant in WM, we used chemoinformatics-based approaches comprised of virtual in silico screening, molecular modeling and target-ligand reverse docking. In silico analysis revealed the antiapoptotic protein BCL2 was the preferential binding partner of nimbolide. The significance of this finding was further tested in vitro in RS4;11 (BCL2-dependent) tumor cells, in which nimbolide induced significantly more apoptosis compared with BCL2 mutated (Jurkat BCL2(Ser70-Ala)) cells. Lastly, intraperitoneal administration of nimbolide in WM tumor xenografted mice, significantly reduced tumor growth and IgM secretion in vivo, while modulating the expression of several proteins as seen on immunohistochemistry. Overall, our data demonstrate that nimbolide is highly active in WM cells, as well as other B-cell cancers, and engages BCL2 to exert its cytotoxic activity.


Asunto(s)
Apoptosis/efectos de los fármacos , Limoninas/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Macroglobulinemia de Waldenström/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Apoptosis/genética , Línea Celular Tumoral , Femenino , Humanos , Células Jurkat , Masculino , Ratones , Ratones SCID , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Macroglobulinemia de Waldenström/genética , Macroglobulinemia de Waldenström/metabolismo , Macroglobulinemia de Waldenström/patología
7.
Blood Cancer J ; 4: e243, 2014 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-25192415

RESUMEN

Second primary malignancies (SPMs) among multiple myeloma (MM) patients have been reported with an estimated incidence varying from 1 to 15%. We have previously reported that significant disparity exists in MM survival across patients of different ethnicities. We undertook a Surveillance Epidemiology and End Results-based analysis to describe the incidence of SPMs among MM patients of different ethnicities, to explore the variable impact that SPMs might have on MM outcomes of patients across racial subgroups. We found that the risk of developing SPMs among MM patients is variable depending on the patient's ethnic background. This warrants further exploration of the impact of SPMs on outcomes of MM patients across different racial subgroups, especially in the form of prospective data collection and analyses.


Asunto(s)
Mieloma Múltiple/etnología , Mieloma Múltiple/epidemiología , Neoplasias Primarias Secundarias/etnología , Neoplasias Primarias Secundarias/epidemiología , Bases de Datos Factuales , Femenino , Humanos , Masculino , Factores de Riesgo
8.
Transpl Infect Dis ; 15(6): E264-7, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24147999

RESUMEN

We report a patient with an autologous stem cell transplant and history of residence in a Chagas disease (CD) endemic area who developed Chagas reactivation after induction for transplantation. We recommend that patients at risk for CD be screened before transplantation, and patients found to have chronic infection be monitored for reactivation post transplant.


Asunto(s)
Anticuerpos Antiprotozoarios/sangre , Trasplante de Médula Ósea , Enfermedad de Chagas/diagnóstico , Acondicionamiento Pretrasplante/efectos adversos , Trypanosoma cruzi/inmunología , Enfermedad de Chagas/sangre , Femenino , Humanos , Persona de Mediana Edad , Mieloma Múltiple/terapia , Reacción en Cadena de la Polimerasa , Recurrencia , Trypanosoma cruzi/genética
9.
Blood Cancer J ; 3: e121, 2013 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-23811785

RESUMEN

Recent studies have reported an increased risk of second primary malignancies (SPM) following multiple myeloma (MM) diagnosis associated with novel anti-myeloma treatments. We evaluated the risk of SPM among 36 491 MM cases reported to the Surveillance, Epidemiology, and End Results program (SEER) between 1973 and 2008. We calculated overall and site-specific standardized incidence ratio (SIR) and 95% confidence intervals (CI) for 2012 SPM cases diagnosed within the 35-year follow-up. There was no significant overall risk of SPM (SIR=0.98; 95% CI=0.94-1.02); however, there were multiple site-specific risk patterns. The risk of breast and prostate cancer was significantly decreased overall and across age, latency and the year of diagnosis strata. There was an ∼50% increased risk of colorectal cancer 5 years after MM diagnosis (Ptrend<0.001). The risk of hematological malignancies was significantly increased, notably for acute myeloid leukemia (AML; SIR=6.51; 95% CI=5.42-7.83). There was a significant decreasing trend for AML over time, particularly for patients 65. However, no significant change in risk was noted after the introduction of autologous stem cell transplant among younger patients (<65 years). On the basis of observed trends for overall SPM as well as AML, no association between the introduction of novel therapies and SPM following MM has emerged in this large population-based study.

10.
J Clin Pharm Ther ; 32(2): 199-202, 2007 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17381671

RESUMEN

OBJECTIVE: To report a case of serotonin syndrome associated with interaction between fentanyl and citalopram, as evidenced by medication history, clinical features and reversal following discontinuation of fentanyl. CASE SUMMARY: A 65-year-old patient chronically treated with the selective serotonin reuptake inhibitor (SSRI) citalopram developed confusion, agitation, tachycardia, tremors, myoclonic jerks and unsteady gait, consistent with serotonin syndrome, following initiation of fentanyl, and all symptoms and signs resolved following discontinuation of fentanyl. Based on the Naranjo probability scale, serotonin syndrome was a probable adverse reaction associated with co-administration of citalopram and fentanyl. DISCUSSION: Serotonin syndrome is a potentially lethal pharmacodynamic interaction between medications that increase serotonergic transmission at the synaptic junction. The development of new pharmacological agents with varied properties and actions has increased the risk of serotonin syndrome as a clinical diagnosis. SSRIs and fentanyl are commonly co-administered, especially in the setting of chronic or malignant pain, as underlying depression may contribute to the pathogenesis of pain. CONCLUSION: Healthcare professionals should be aware of the possible development of serotonin syndrome as a complication of initiation of fentanyl and other phenylpiperidine opioids in patients treated with SSRIs.


Asunto(s)
Citalopram/efectos adversos , Interacciones Farmacológicas , Fentanilo/efectos adversos , Síndrome de la Serotonina/inducido químicamente , Anciano , Citalopram/uso terapéutico , Quimioterapia Combinada , Fentanilo/uso terapéutico , Humanos , Síndromes Mielodisplásicos/tratamiento farmacológico , Trastornos Mieloproliferativos/tratamiento farmacológico , Síndrome de la Serotonina/diagnóstico , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico
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